Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:5.99.1.2 (topoisomerase)
 9,166 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

XK469 (NSC 697887; (+/-)-2-[4-(7-chloro-2-quinoxaliny)oxy]phenoxy propionic acid), an analog of the herbicide Assure, which possesses antitumor activity, especially against murine solid tumors and human xenografts, has recently been found to be the first topoisomerase IIbeta poison. Both R(+) and S(-) isomers are cytotoxic, although the R-isomer is more potent. Using a chiral high-performance liquid chromatography assay, pharmacokinetics of R(+)-, S(-)-, and (+/-)-XK469 in Fischer-344 rats were investigated following their separate i.v. administrations. S(-)-XK469 was found to be predominantly converted to the R-isomer in circulation when the S-isomer was administered either alone or as a racemic mixture. No trace of the S-isomer was found in circulation or in urine or feces, following the R-isomer administration, up to 72 h. In the rat, the plasma concentration-time profiles for both isomers follow a two-compartment pharmacokinetics with the mean t(1/2beta) for the R-isomer of 24.7 h being significantly longer than 4.2 h, the mean t(1/2beta) for the S-isomer. The mean total clearance of the S-isomer was over 200-fold more rapid than that of the R-isomer, and the major clearance route of the S-enantiomer was inversion to its antipode, as estimated by the fractional formation clearance of R(+)-XK469 of 0.93. Protein binding for both enantiomers was in the range of 95 to 98%. Urinary and fecal elimination in 72 h as the intact drug were 7 to 10% and 8% of the administered dose, respectively, either administered as the individual enantiomers or as a racemate. Cumulative biliary elimination in 7 h was about 3% of the dose. No evidence of enantiomeric interaction at the pharmacokinetic level was detected.
 ...
PMID:Chiral pharmacokinetics and inversion of enantiomers of a new quinoxaline topoisomerase IIbeta poison in the rat. 1185 56

The role of DNA topoisomerase (Topo) IIbeta in cancer chemotherapy remains unclear, although this particular isoform has been implicated in drug resistance. In this study, we investigated Topo IIbeta as a target for 2-[4-(7-chloro-2-quinoxalinyloxy)phenoxy]-propionic acid (XK469), a novel synthetic quinoxaline phenoxypropionic acid derivative, in a Waldenstrom's macroglobulinemia (WM) model. In vitro, the WSU-WM cell line was exposed to 1.0, 2.0, 5.0, 8.0, and 10 microM XK469. Our results demonstrate a concentration-dependent cell growth inhibition with a concentration-independent inhibition of Topo IIbeta, as determined by band depletion assay. The cell growth inhibition of cells correlated well with increase in Bax:Bcl-2 ratio and poly(ADP-ribose) polymerase (PARP) cleavage. We used our established WSU-WM severe combined immunodeficient mouse xenograft model to test the efficacy and effect of XK469 on Topo IIbeta in vivo. Topo IIbeta was inhibited equally using two different dose schedules (20 and 40 mg/kg, i.v., for a total of 120 and 240 mg/kg, respectively); however, there was no significant decrease in tumor weight. Western blot analysis of cells isolated from s.c. tumors showed no induction of the Bax protein and a very low Bax:Bcl-2 ratio of approximately 0.3 in correlation with minimum PARP cleavage. Our study shows that XK469 inhibits Topo IIbeta in WSU-WM cells both in vitro and in vivo at or below the maximum tolerated dose in severe combined immunodeficient mice. However, there was no change of apoptosis-related molecules such as PARP, Bax, and Bcl-2 or reduction in tumor weight in association with Topo IIbeta inhibition. We conclude that Topo IIbeta inhibition by XK469 as a target is not sufficient for therapeutic effects in WSU-WM.
 ...
PMID:2-[4-(7-chloro-2-quinoxalinyloxy)phenoxy]-propionic acid (XK469) inhibition of topoisomerase IIbeta is not sufficient for therapeutic response in human Waldenstrom's macroglobulinemia xenograft model. 1251 64